Abstract 2402: Matrix Metalloproteinases and their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural and Functional Changes and to Light Chain Amyloid Deposition in the Heart

Abstract

Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix disruption. Systemic deposition of immunoglobulin light chain (LC) fibrils (AL or “primary”) amyloidosis can lead to cardiac amyloidosis with heart failure. AL cardiomyopathy (AL-CMP) has an accelerated clinical course and a worse prognosis compared to non-LC cardiac amyloidoses. We therefore tested the hypothesis that determinants of proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), would have distinct patterns and contribute to the pathogenesis of AL-CMP. We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with non-LC cardiac amyloidosis: i.e. amyloidosis associated with either wild-type transthyretin (TTR), senile systemic amyloidois (SSA) or a mutant TTR (ATTR), and 10 patients with AL amyloidosis without cardiac involvement. Plasma MMP-2, MMP-9, TIMP-1, TIMP-2 and TIMP-4, brain natriuretic peptide (BNP) values and echocardiographic parameters were determined. AL-CMP and non-LC groups had similar degrees of increased left ventricular wall thickness (LVWT) and mass index (LVMI). However, BNP, MMP-9 and TIMP-1 levels were distinctly elevated and accompanied by marked diastolic dysfunction in the AL-CMP group vs. no or minimal increases in the non-LC group. BNP, MMPs and TIMPs were not associated with the degree of LVWT but were to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in non-LC hearts. Despite comparable LVWT and LVMI with non-LC cardiac amyloidosis, AL-CMP patients have higher BNP, MMP-9 and TIMP-1, which correlated with diastolic dysfunction. These findings suggest a relationship between LC and extracellular matrix proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP.